Cartilage destruction in rheumatoid arthritis results from (1) direct invasion/degradation by synovial pannus and (2) response to a soluble synovial factor(s) ("catabolin") that stimulates chondrocyte catabolic activity. Both mechanisms will be studied in human articular cartilage cocultured with rheumatoid synovium or its products. Proteoglycan and collagen breakdown and the responses to antirheumatic drugs will be quantified and compared to an established heterologous system employing bovine nasal cartilage. Products released from prelabeled cartilage will be characterized by sedimentation, chromatographic and digestion methods. 35S-Sulfate Uptake by cartilage during and after synovium exposure will assess suppression and capacity for "repair" of cartilage biosynthetic activity. Catabolin production in synovial cultures will be assessed by a cartilage disc bioassay using purified porcine catabolin as standard. Cell interactions potentially important in catabolin production will be examined in rheumatoid synovial cell cultures exposed to lectin-activated mononuclear cells. The actions of human and porcine catabolin will be compared in terms of onset and time course of cartilage breakdown, requirement for continued catabolin exposure, nature of degradation products and cartilage histology. Specific proteoglycanase and collagenase activities will be sought in cartilage media my means of a labeled proteoglycan-collagen mixed gel assay. Early cellular events in cartilage that precede degradation will be compared in catabolin-treated cartilage and chondrocyte cultures. Requirements for early protein and RNA synthesis measured by precursor incorporation in the presence or absence of inhibitors will be correlated with the subsequent appearance of cartilage enzymes and breakdown products. Glucocorticoid effects on synovial catabolin production vs. cartilage catabolin response, dose relationships for each and the critical time for hormone action in regulating catabolin function will be determined. Inhibitor studies of catabolin synthesis and release will be extended to rheumatoid synovial cell cultures, and hormone effects on mononuclear-synovial cell interactions affecting catabolin production will be explored. Clarification of these events is essential for understanding the cellular basis of cartilage breakdown in the rheumatoid lesion. In turn, this will help in designing rational pharmacologic and radiation therapies plus methods for their delivery.